Antagonists

Although recently, two small, non-peptidergic compounds were discovered (Fig. 16.6) by random screening of large chemical libraries and libraries of natural products, and both these compounds behave as antagonists at galanin receptors (Puar et al. 2000; Scott et al. 2000). One of these compunds, spirocoumaranon (Sch 202596), is a fungal metabolite, which binds to human GalRl with an IC50 of 1.4 ^M. The other one, dithiepine-1,1,4,4-tetroxide (from Johnson and Johnson), has an IC50 of 0.17 ^M at the human GalR1. These compounds however, have low affinity, no galanin receptor subtype specificity, and their chemical structure is not ideal for future medicinal chemistry development. In addition, since galanin is not a member of a family of peptides, few endogenous cross-reactive ligands are expected to be found at this point. The number of receptor subtypes might although increase. Hence, the compounds that are now beginning to evolve will have to be refined in terms of subtype specificity and affinity, for these to be useful as ligands to distinguish different subtypes of the galanin receptor.

Table 16.5 Pharmacological application of galanin receptor subtype-specific ligands

Subtype Site specificity of action

Indication

Neurochemical effects to be measured

Type I Hippocampus Anticonvulsant Neuroprotection,

Ischaemia LC, DRN Antidepressant

Spinal cord Analgesia, Allodynia

Type I/II

Nucleus basalis 'Trophic factor' Hippocampus/LC

Disease modifier Alzheimer's disease Cognitive enhancer

Cholinergic Neuron survival f Ach f, NE f

Type II/III

Pituitary Hypothalamus

Dwarfism Feeding disorder

GH t

Modification of leptin, NPY, DA response

GalR2 also binds chimeric peptides consisting of the N-terminal part of galanin (galanin (1-13)) covalently connected to sequences derived from other known peptides . The chimeric peptides M15, M35, and M40 (Table 16. 5) proved to be high affinity antagonists in most in vivo experiments, and were helpful in defining the roles of galanin . However, when used in very high concentrations in vitro, these chimeric peptides act as partial agonists because they all present the galanin (1-13) sequence .

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